This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lung cancer is by far the leading cause of cancer death in both men and women in the United States (1-3). Successful treatment of lung cancer requires early diagnosis. However, the vast majority of lung cancer is diagnosed at late stage when survival is poor. Improved methods for imaging and diagnosing lung cancers are needed. With improvements in resolution, contrast and probes, optical coherence tomography (OCT) offers the potential to help achieve this objective. We propose that in the future multimodality optical imaging, combining autofluorescence, ultrahigh resolution OCT, and multi-photon/confocal endoscopy may ultimately provide a fully effective approach to this problem. This proposal addresses the initial phases of this concept: development and optimization of OCT for diagnosis of early airway cancer. We propose that high resolution, in-vivo thoracic endoscopic three dimensional (3-D) OCT can help diagnose malignancy-related surface and subsurface morphological and structural changes in order to advance bronchoscopic airway cancer diagnostic capabilities. The objectives of the proposed research are to: 1) develop real-time high speed flexible fiberoptic and rigid endoscopic techniques for 3-dimensional near histologic-resolution optical visualization of airway and pleural malignant pathophysiologic changes, 2) enhance optical contrast to improve diagnostic imaging discrimination, 3) translate and optimize this technology in animal models, and 4) apply endoscopic OCT technology in-vivo in clinical studies to demonstrate feasibility for improving sensitivity and specificity of diagnosis and treatment in patients with bronchogenic airway cancers. The specific aims of this proposal are to: 1. Develop, integrate, and utilize i) small diameter flexible fiberoptic 3-D bronchoscopic MEMS based, and ii) rigid endoscopic 3-D OCT probes. 2. Develop and test antibody directed gold nano-particle liposomal OCT tissue contrast enhancement methods. Image normal and malignant excised animal model tissue with OCT, enhanced tissue contrast agent OCT, and compare structural images to histology. 3. Evaluate F-OCT endoscopy designs and contrast enhancement methods using oral cancer and pleural tumor animal models in initial pre-clinical animal studies to advance technical delivery, contrast, and analytical methods for subsequent application to clinical airway malignancy, 4. Image human airway and pleural specimens with the following categories of presentations: 1- normals, 2 [unreadable]metaplasia, 3 [unreadable]malignant neoplasia, and 4- benign "negative control" airway abnormalities including granulomas, strictures, and granulation tissue to determine capabilities of 3-D F-OCT diagnostic parameters of resolution, depth of penetration, and ability to differentiate pathologic abnormalities. 5. Perform clinical investigations to demonstrate high resolution endoscopic F-OCT feasibility for early endobronchial cancer detection and the ability to diagnose endobronchial cancer with improved specificity and sensitivity compared to histology.